Design, Optimization and Synthesis of Certain Heterocyclic Compounds with Potential Targeted Anticancer Activity

Abstract

“Design, optimization and synthesis of certain heterocyclic compounds with potential targeted anticancer activity”

Cancer is a generic term for a large group of diseases that can affect any part of the body. It is characterized by an imbalance of cell replication and cell death that favors growth of a tumor cell population. Cancer chemotherapy has been one of the major medical advances. In the last 2 decades, researchers focused on developing targeted cancer therapies by specifically inhibiting protein kinases; e.g.,: EGFR tyrosine kinases that have crucial roles in mediating cell growth signaling pathway. The inhibition of EGFR is considered as an important target of many classes of anticancer compounds as targeted therapy. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue of more potent novel anticancer agents development. Extending the reported work strategy to create novel potent EGFR inhibitors, novel optimization strategy, our recently reported quinoline-3-carboxamide compound (45) (EGFR IC50 = 5.283 µM & MCF-7 IC50 = 3.46 μM) was applied concerning 4- and /or 6- position hopping to create more potent EGFR inhibitors having remarkable improved anticancer activity. Two classes of target quinoline-3-carboxamide compounds were designed and synthesized [guided by the essential pharmacophoric features of the approved anticancer drugs Lapatinib (27) and Gefitinib (28)]. Class (1) target compounds bear α, β-unsaturated ketone moiety at position 6 IXa-o while class (2) compounds have five membered ring (thiophene Xa-c or thiazole XIa-c) at the same position or benzyloxy moiety at position 4 XIV. All the newly synthesized target compounds were subjected to EGFR TK enzyme assay. Then, the most biologically active compound was subjected for further optimization. Finally, the most potent quinoline-3-carboxamide derivative in each class was converted to the 3-carbonitile analogue for further exploration of the activity through measuring their EGFR IC50. The most potent quinoline-3-carboxamides were IXo, Xb and XIV that showed EGFR IC50 values 2.61, 0.49 and 1.73 μM, respectively. Furthermore, the anticancer activity of six compounds IXo, IXp, Xb, XIIa, XIIb and XIV exhibiting potent EGFR inhibition was evaluated on the MCF-7 cell line showing MCF-7 IC50 values 3.355, 3.647, 5.069, 3.617, 0.839 and 10.85 μM, respectively.